The Impact of Phenylketonuria on Body Composition in Adults.

INTRODUCTION: Patients with phenylketonuria (PKU) must follow a lifelong phenylalanine (Phe)-restricted diet with additional amino acid supplementations, and this may put them at risk for nutritional disturbances. However, the body composition and nutritional status of adult patients with PKU has only been partially explored. The current study aims to assess the body composition of adult patients with PKU using multifrequency bioimpedance analysis (MF-BIA) and to reveal potential correlations between therapy adherence and body composition. Additionally, we compared body composition of patients with healthy controls. METHODS: Fifty adult patients with early-treated PKU (27 female and 23 male) and 40 healthy, age- and gender-matched controls were included in this single-center, cross-sectional study. MF-BIA was performed on all subjects. Additionally, we determined serum nutritional markers for all patients. In the PKU patient group, correlation analyses were performed between body composition parameters and therapy adherence. We compared body composition of patients with PKU and controls using BIA. RESULTS: The proportion of overweight was 56% among all patients with PKU. Female patients with PKU had significantly higher body fat percentage compared with controls. In parallel with higher fat content, we observed lower muscle mass, protein, and mineral content among female patients with PKU compared to controls. Such findings were not observed in male patients. Female patients with PKU had decreased therapy adherence and had significantly lower prealbumin levels compared with males. There was no significant correlation observed between body composition parameters and therapy adherence over the last 10 years in the PKU patient group. CONCLUSION: Although female patients had less optimal therapy adherence over the last 10 years compared with male patients, our results suggest that this does not influence body composition fundamentally. Our results suggest that obesity is an important comorbidity in young adult patients with PKU, especially in females. We advocate that nutritional assessments and weight management should be additional objectives of PKU management to provide optimal care.

Effects of intraoperative positive end-expiratory pressure optimization on respiratory mechanics and the inflammatory response: a randomized controlled trial.

Applying lung protective mechanical ventilation (LPV) during general anaesthesia even in patients with non-injured lungs is recommended. However, the effects of an individual PEEP-optimisation on respiratory mechanics, oxygenation and their potential correlation with the inflammatory response and postoperative complications have not been evaluated have not been compared to standard LPV in patients undergoing major abdominal surgery. Thirty-nine patients undergoing open radical cystectomy were enrolled in this study. In the study group (SG) optimal PEEP was determined by a decremental titration procedure and defined as the PEEP value resulting the highest static pulmonary compliance. In the control group (CG) PEEP was set to 6 cmH2O. Primary endpoints were intraoperative respiratory mechanics and gas exchange parameters. Secondary outcomes were perioperative procalcitonin kinetics and postoperative pulmonary complications. Optimal PEEP levels (median = 10, range: 8-14 cmH2O), PaO2/FiO2 (451.24 ± 121.78 mmHg vs. 404.15 ± 115.87 mmHg, P = 0.005) and static pulmonary compliance (52.54 ± 13.59 ml cmH2O-1 vs. 45.22 ± 9.13 ml cmH2O-1, P < 0.0001) were significantly higher, while driving pressure (8.26 ± 1.74 cmH2O vs. 9.73 ± 4.02 cmH2O, P < 0.0001) was significantly lower in the SG as compared to the CG. No significant intergroup differences were found in procalcitonin kinetics (P = 0.076). Composite outcome results indicated a non-significant reduction of postoperative complications in the SG. Intraoperative PEEP-optimization resulted in significant improvement in gas exchange and pulmonary mechanics as compared to standard LPV. Whether these have any effect on short and long term outcomes require further investigations. Trial registration: Clinicaltrials.gov, identifier: NCT02931409.

The Association of Therapy Adherence and Thyroid Function in Adult Patients with Phenylketonuria.

BACKGROUND: The standard, lifelong therapy of phenylketonuria (PKU) is a natural protein-restricted diet complemented with phenylalanine (Phe)-free L-amino acid mixtures that provide the daily necessary micronutrients. OBJECTIVE: To assess thyroid function and structure and the iodine status of early-treated adult PKU (ETPKU) patients in Hungary. METHODS: Sixty-nine PKU patients (aged 18-41 years) and 50 healthy controls were enrolled in the study. Thyroid hormones, serum thyroglobulin, thyroid antibodies, urinary iodine, and selenium concentrations were measured, and thyroid ultrasound was performed. RESULTS: The incidence of thyroid dysfunction was infrequent (n = 2). Blood Phe was negatively correlated with thyroid-stimulating hormone (TSH), and PKU patients had higher free thyroxine and lower TSH levels than healthy controls. Although optimal iodine status was found in the entire PKU population, by dividing the patients according to their therapy compliance, we observed that lower therapy adherence was associated with mild iodine deficiency and lower urinary selenium levels. CONCLUSIONS: The results of this study suggest that iodine status is strongly influenced by the adherence to therapy in ETPKU patients. No or not enough medical food consumption combined with a low-Phe diet can lead to subclinical iodine deficiency.

[Diet treatment of classical galactosemia]. / Klasszikus galactosaemia dietetikai kezelési lehetoségei.

Classical galactosemia is an inherited disorder of the carbohydrate metabolism, most often caused by the deficient activity of the enzyme galactose-1-phosphate-uridyltransferase. Classical galactosemia presents in the neonatal period with life threatening illness after galactose is introduced in the diet. Symptoms and signs include poor feeding, vomiting, and diarrhea, weight loss, jaundice, hypotension, cataracts, hepatosplenomegaly, hepatocellular insufficiency, and encephalopathy. Since 1975 the testing for galactosemia is part of the neonatal screening program in Hungary. Affected newborns are recognized in the first days of their life, and special diet is introduced immediately. The therapy of galactosemia is the lactose-free and galactose-poor diet for life. As a result of the nationwide newborn screening and the lifelong medical therapy, early treatment with galactosemia can achieve a normal life without serious complications. Orv Hetil. 2017; 158(47): 1864-1867.

[Maternal phenylketonuria]. / Maternális phenylketonuria.

Elevated maternal phenylalanine levels during pregnancy are teratogenic, and may result in embryo-foetopathy, which could lead to stillbirth, significant psychomotor handicaps and birth defects. This foetal damage is known as maternal phenylketonuria. Women of childbearing age with all forms of phenylketonuria, including mild variants such as hyperphenylalaninaemia, should receive detailed counselling regarding their risks for adverse foetal effects, optimally before contemplating pregnancy. The most assured way to prevent maternal phenylketonuria is to maintain the maternal phenylalanine levels within the optimal range already before conception and throughout the whole pregnancy. Authors review the comprehensive programme for prevention of maternal phenylketonuria at the Metabolic Center of Budapest, they survey the practical approach of the continuous maternal metabolic control and delineate the outcome of pregnancies of mothers with phenylketonuria from the introduction of newborn screening until most recently.

A retrospective analysis of metabolic control in children with PKU in the COVID-19 era.

Background: Patients with phenylketonuria (PKU) must maintain a lifelong natural protein-restricted diet to prevent neuro-cognitive damage. Early diagnosis is established with newborn screening, with diet subsequently controlled by regular phenylalanine (Phe) monitoring. During the COVID-19 pandemic, significant lockdown measures were introduced that may have influenced the above. Aim of our study: To establish whether the diagnosis was delayed in neonates during the pandemic. In addition, metabolic control was further assessed during the COVID-19 pandemic era (CE) compared to the same period a year prior (non-COVID-19 era, NCE). The lockdown periods (LD) were also compared with unrestricted periods (URP). Patients methods: Six neonates born during the CE and eight neonates born during NCE were included in the newborn screening analysis. Seventy-two classical PKU patients aged 2-18 years and categorized as children (2-12 years; 51 patients) and adolescents (>13 years; 21 patients) were included in the metabolic control analysis. The frequency of dried blood spot (DBS) sampling and Phe levels were assessed according to the different periods. Results: There was no diagnostic or therapeutic delay in reaching the recommended Phe range in neonates born during CE compared to those born in NCE (median [interquartile range, IQR]: 23.5 [22.5-24] vs. 22 [18.0-27] days, p = NS). The cumulative DBS sampling frequency in children increased by 9.9% in the CE while no change was noted in the adolescent group. The median Phe level increased significantly in both age groups in the CE, but remained within the recommended target range. During CE, changes in Phe levels differed in the two age groups: children had the highest median Phe in the second lockdown period (LD2), while the adolescents had an increased Phe in URP.There were significant negative correlations between DBS sampling frequencies and Phe levels in both age groups in NCE (children: r - 0.43, p = 0.002; adolescents r = -0.37, p = 0.012), and in adolescents in CE (r = -0.62, p = 0.006). Conclusion: The pandemic did not impact newborn metabolic screening. The increased frequency of DBS sampling in CE and good target Phe levels suggest a better compliance in a very sensitive period. Since many factors may impact metabolic control in the different age groups, further studies are needed to analyse their respective role.

Joint efforts for saving vision: overview of the prevention of vision loss inside and outside Hungary / Összefogás a látás védelmében: körkép a látásromlás prevenciójának hazai és nemzetközi helyzetérol.

Összefoglaló. Az Egészségügyi Világszervezet (WHO) Látásról szóló világjelentése (World report on vision 2019) szerint a népesség növekedése és elöregedése világszerte növekvo számban vezet mérsékelt vagy súlyosabb fokú látáskárosodáshoz. A WHO adatai szerint napjainkban 1,1 milliárd személy él a látáskárosodás valamely formájával, melyek mintegy 80%-a megelozheto lenne. A látáskárosodott vagy látáskárosodással veszélyeztetett személyek 90%-a ugyan alacsony vagy közepes humán fejlettségu országban él, de a rövidlátás és a cukorbetegség miatti retinopathia okozta látáskárosodások száma a magas és a nagyon magas humán fejlettségu országok csoportjában is emelkedik. A WHO elorejelzései szerint ezzel a tendenciával 2050-re 61 millióan élnek majd vaksággal, és 1,7 milliárd személy lehet csökkentlátó világszerte. Riasztó adat, hogy az emberiség 23%-a rövidlátó, de a jelenlegi növekedési tendenciák alapján 2050-re az elofordulás már 50%-os lehet. A vakság, illetve a látáskárosodás megelozése és a látásrehabilitáció fejlodése érdekében a WHO globális akcióprogramjainak (VISION 2020, World report on vision) ismertetésén túl tanulmányunk bemutatja a hazai intézkedéseket és a populációalapú felmérések nemzetközi és hazai eredményeit, köztük a látásromlás legfobb kórokait és a látáskárosodáshoz leggyakrabban vezeto szembetegségeket. Tanulmányunkban bemutatjuk a látáskárosodással élo gyermekek hazai, egészségügyi és pedagógiai szempontból releváns populációjellemzoit is. Összefoglalónk célja felhívni a figyelmet arra, hogy a látáskárosodás megelozése és a kialakult látáskárosodással élo emberek komplex rehabilitációja nemcsak a szemészeti szakma feladata, hanem be kell, hogy épüljön az egészségügyi alapellátáson túl az oktatási és szociális rendszerekbe is. Orv Hetil. 2021; 162(30): 1187-1197. Summary. World Health Organization's (WHO) World report on vision (2019) underlines that the increasing size and age of the population leads to a general growth in cases of vision impairment of varying severity (moderate and severe vision impairment). According to WHO data, globally 1.1 billion individuals live with vision impairment, and approximately 80% of all cases is preventable. While around 90% of people with vision impairment or at risk of vision impairment live in low- or middle-income countries, the prevalence of near vision impairment and diabetic retinopathy is increasing in high-income countries, too. WHO assumes that if this tendency is not interrupted, by 2050 61 million individuals will be blind and 1.7 billion individuals will have vision impairment. It is rather frightening that currently 23% of the world's population is diagnosed with near vision impairment, and with this tendency by 2050 this number may reach 50%. Our study takes a closer look at global actions for preventing vision loss and vision impairment together with the joint efforts to improve vision rehabilitation services, and briefly introduces Hungarian measures, results of international and national population-centred research results, and the major causes of vision impairment. Then, the Hungarian population of children with vision impairment is characterised from both healthcare and pedagogical perspectives. The objective of this review is to point out that the prevention of vision impairment and comprehensive rehabilitation of persons with vision impairment requires joint efforts from ophthalmology, pedagogy and social services. Orv Hetil. 2021; 162(30): 1187-1197.

Quality of life in children living with PKU - a single-center, cross-sectional, observational study from Hungary.

BACKGROUND: Phenylketonuria (PKU) is an inherited error of metabolism, screened at 48-72 h of life since 1975 in Hungary. The patients have to keep a strict lifelong protein-restricted diet, resulting in PKU and its treatment can lead to social and financial burdens. The current study aimed to evaluate the health-related quality of life (HRQoL) of children living with PKU. PATIENTS AND METHODS: A single-centre, cross-sectional, observational study was conducted at the Center of Newborn Screening and Inherited Metabolic Disorders of Budapest, Hungary, using the PKU-quality of life (PKU-QoL) questionnaire. Responses of 59 parents and 11 teenagers were collected. Numerous aspects regarding HRQoL were analysed according to clinical compliance and severity. The patients were classified into groups with good or suboptimal adherence based on regular phenylalanine (Phe) values. The online officially translated versions of the adolescent or parental PKU-QoL questionnaire were used and analysed anonymously. Differences in HRQoL were compared - PKU vs. Hyperphenylalaninaemia (HPA) and good vs. suboptimal adherence. RESULTS: Twenty-five of 32 examined parameters had no or little impact on HRQoL. The most frequently reported symptom was irritability. Food enjoyment was the most impacted domain, with a major severity score in the adolescent group (median 62,5, IQR: 25-75). The emotional impact was scored at moderate severity by both the adolescents and parents. Classical PKU patients with good metabolic control were more frequently tired than HPA patients (0,0027). The group with poor metabolic adherence showed more frequent tiredness (p = 0,03), slow thinking (p = 0,018) and anxiety (p = 0,015). CONCLUSION: Overall, our patients showed an excellent HRQoL; most domains (29/36) were reported as little/no impacted. Worse QoL was found in patients with suboptimal metabolic control. Particular attention should be paid to the emotional health of PKU patients.

[Large deep venous thrombosis in childhood--three cases]. / Gyermekkori nagy kiterjedésû mélyvénás trombózis három eset kapcsán.

Deep venous thrombosis is a rare disease in children under the age of 18, with an estimated incidence of 1/100,000 per year in Hungary. Its typical localization in children is in the extremities, usually occurring in newborns and in teenagers. Both congenital and acquired risk factors can be in the background. Although it is a rarity, we should think of it, because late diagnosis can cause life-threatening conditions like pulmonary embolism or central nervous system thrombosis. Detailed medical history can help the diagnosis. Etiology, possible congenital and acquired risk factors, as well as diagnostic and therapeutic options are discussed through three cases of teenage children. Diagnostic difficulties of deep venous thrombosis in childhood are the following: the occurrence is rarer than in adulthood therefore it is often forgotten as a possible diagnosis, coagulation parameters are age-dependent, and diagnosis with imaging techniques is more difficult.

Health Related Quality of Life assessment among early-treated Hungarian adult PKU patients using the PKU-QOL adult questionnaire.

BACKGROUND: The implementation of neonatal screening and the early initiation of lifelong therapy have helped to prevent severe complications and enabled much more favorable outcomes for early-treated phenylketonuria (ETPKU) patients. However, PKU patients tend to develop subtle cognitive and psychosocial abnormalities and the strict dietary therapy can present financial and social burden. Thus, PKU is expected to affect the quality of life (QoL) of these patients. There is insufficient evidence regarding the relationship between metabolic control and Health-Related QoL (HRQoL). We aimed to assess the effect of short- and long-term therapy on QoL among Hungarian adult PKU patients using the standardized PKU-specific PKU-QoL questionnaire. Methods: We conducted a single-centre, cross-sectional, observational study in Hungary. We included adult PKU patients treated with diet and amino acid supplements only. Patients reported HRQoL using the standardized adult PKU-QoL questionnaire and mean blood Phe concentrations were assessed for three different time periods: the previous 10 years, the previous year and concentration at the time of completing the questionnaire. The correlation between patients' QoL scores and their Phe levels was assessed. The classical PKU group was further divided into "good" and "suboptimal" adherence groups based on individual mean Phe levels in the examined time period. We evaluated differences in QoL among the two subgroups of classical PKU patients. QoL scores between classical and non-classical patients were also compared. Results: Data from 88 adult patients were analysed (66 had classical PKU). No median PKU-QoL score reached major or severe impact/frequent symptoms in any domain. The highest scores (meaning larger burden) were mostly related to emotional impact of PKU and disease management. When performing correlation analysis between Phe levels and QoL scores by all patients we found weak to fair positive correlation in several domains either short or long term. Patients with classical PKU reported greater financial impact of PKU than patients with less severe PKU. Classical PKU patients with good therapy adherence tended to report better HRQoL scores than patients with suboptimal adherence. Conclusion: We conclude that patients showed good HRQoL using the PKU-specific questionnaire. Our study demonstrates that suboptimal metabolic control is negatively associated with patients' HRQoL.

Metabolic and catecholamine response to sympathetic stimulation in early-treated adult male patients with phenylketonuria.

PURPOSE: Defective function of phenylalanine hydroxylase in phenylketonuria (PKU) results in the accumulation of phenylalanine (Phe) and the reduction of tyrosine (Tyr) in the blood, interfering in the normal development and function of organs and tissues in the body. Tyr is the precursor of catecholamines, secreted in response to stress by the adrenal medulla and paraganglia. The aim of this study was to evaluate plasma catecholamine and amino acid response to an escalating series of sympathetic stress tests in PKU patients. METHODS: Twelve males with classical PKU (aged 18-41 years) and ten healthy male controls were included in this study. The subjects were exposed to three different sympathetic stress stimulations: cold pressor, isometric handgrip, and peak treadmill tests to exhaustion. Physiological, metabolic, and hormonal changes were determined. RESULTS: Aerobic capacity (VO2max) was significantly lower in the PKU group (p = 0.018); however, relative VO2max was similar in the two groups during the spiroergometric test. No significant differences in norepinephrine or in epinephrine response were found between the two groups during the different stimulation tests. Blood Phe increased significantly in the PKU group compared with controls (p = 0.027) during the spiroergometric test, while Tyr levels remained stable in both groups. CONCLUSION: PKU itself might not influence stress-induced catecholamine changes. Only strenuous exercise increased blood Phe levels in PKU subjects.

Perioperative Lung Protective Ventilatory Management During Major Abdominal Surgery: A Hungarian Nationwide Survey.

Lung protective mechanical ventilation (LPV) even in patients with healthy lungs is associated with a lower incidence of postoperative pulmonary complications (PPC). The pathophysiology of ventilator-induced lung injury and the risk factors of PPCs have been widely identified, and a perioperative lung protective concept has been elaborated. Despite the well-known advantages, results of recent studies indicated that intraoperative LPV is still not widely implemented in current anaesthesia practice. No nationwide surveys regarding perioperative pulmonary protective management have been carried out previously in Hungary. This study aimed to evaluate the routine anaesthetic care and adherence to the LPV concept of Hungarian anaesthesiologists during major abdominal surgery. A questionnaire of 36 questions was prepared, and anaesthesiologists were invited by an e-mail and a newsletter to participate in an online survey between January 1st to March 31st, 2018. A total of one hundred and eleven anaesthesiologists participated in the survey; 61 (54.9%), applied low tidal volumes, 30 (27%) applied the entire LPV concept, and only 6 (5.4%) regularly applied alveolar recruitment manoeuvres (ARM). Application of low plateau and driving pressures were 40.5%. Authoritatively written protocols were not available resulting in markedly different perioperative pulmonary management. According to respondents, the most critical risk factors of PPCs are chronic obstructive pulmonary diseases (103; 92.8%); in contrast malnutrition, anaemia or prolonged use of nasogastric tube were considered negligible risk factors. Positive end-expiratory pressure (PEEP) and regular ARM are usually ignored. Based on the survey, more attention should be given to the use of LPV.

Effects of intraoperative PEEP optimization on postoperative pulmonary complications and the inflammatory response: study protocol for a randomized controlled trial.

BACKGROUND: Patients undergoing general anesthesia and mechanical ventilation during major abdominal surgery commonly develop pulmonary atelectasis and/or hyperdistention of the lungs. Recent studies show benefits of lung-protective mechanical ventilation with the use of low tidal volumes, a moderate level of positive end-expiratory pressure (PEEP) and regular alveolar recruitment maneuvers during general anesthesia, even in patients with healthy lungs. The purpose of this clinical trial is to evaluate the effects of intraoperative lung-protective mechanical ventilation, using individualized PEEP values, on postoperative pulmonary complications and the inflammatory response. METHODS/DESIGN: A total number of 40 patients with bladder cancer undergoing open radical cystectomy and urinary diversion (ileal conduit or orthotopic bladder substitute) will be enrolled and randomized into a study (SG) and a control group (CG). Standard lung-protective ventilation with a PEEP of 6 cmH2O will be applied in the CG and an optimal PEEP value determined during a static pulmonary compliance (Cstat)-directed PEEP titration procedure will be used in the SG. Low tidal volumes (6 mL/Kg ideal bodyweight) and a fraction of inspired oxygen of 0.5 will be applied in both groups. After surgery both groups will receive standard postoperative management. Primary endpoints are postoperative pulmonary complications and serum procalcitonin kinetics during and after surgery until the third postoperative day. Secondary and tertiary endpoints will be: organ dysfunction as monitored by the Sequential Organ Failure Assessment Score, in-hospital stay, 28-day and in-hospital mortality. DISCUSSION: This trial will assess the possible benefits or disadvantages of an individualized lung-protective mechanical ventilation strategy during open radical cystectomy and urinary diversion regarding postoperative pulmonary complications and the inflammatory response. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02931409 . Registered on 5 October 2016.

Serum prolactin as a biomarker for the study of intracerebral dopamine effect in adult patients with phenylketonuria: a cross-sectional monocentric study.

BACKGROUND: It has been previously postulated that high phenylalanine (Phe) might disturb intracerebral dopamine production, which is the main regulator of prolactin secretion in the pituitary gland. Previously, various associations between Phe and hyperprolactinemia were revealed in studies performed in phenylketonuria (PKU) children and adolescents. The aim of the present study was to clarify whether any relation between serum phenylalanine and prolactin levels can be found in adult PKU patients. PATIENTS AND METHODS: We conducted a cross-sectional, monocentric study including 158 adult patients (male n = 68, female n = 90) with PKU. All patients were diagnosed during newborn screening and were treated since birth. Serum Phe, tyrosine (Tyr), prolactin (PRL), and thyroid-stimulating hormone (TSH) levels were measured, and Phe/Tyr ratio was calculated. Males and females were analyzed separately because the serum prolactin level is gender-dependent. RESULTS: No significant correlations were found between serum phenylalanine, tyrosine, or the Phe/Tyr ratio and serum prolactin level either in the male or in the female group. CONCLUSIONS: In treated adult PKU patients, the serum prolactin level may not be significantly influenced by Phe or Tyr serum levels.

Sentinel node detection in malignant melanoma patients: radiation safety considerations.

BACKGROUND: The surgical management of malignant melanoma necessitates correct sentinel lymph node localization. The highest reported sensitivities are those of lymphoscintigraphy and intraoperative gamma-probe detection combined with a vital blue dye technique. OBJECTIVE: Control of the radiation doses experienced by surgical personnel untrained in the use of unsealed radioactive materials. METHODS: Sentinel lymph nodes were localized, and biopsies were performed in 25 patients with malignant melanoma. Radiation doses during surgery were determined with energy-compensated silicon pin diode detectors and LiF thermoluminescent ring dosimeters. RESULTS: In 21 cases (24%), the measured doses were less than 1 microSv, but in 4 operations (16%), 1 to 4.5 microSv was received. The equivalent dose rate was generally less than 1 microSv/h. The finger-absorbed doses for the surgeon and the assistant surgeon were (mean+/-SD) 159+/-23 and 48+/-17 microGy per intervention, respectively. CONCLUSION: Personal dosimetric survey and limitation of the number of surgical interventions do not appear to be essential.